The study of the biochemical mechanisms that regulate the utilization of alternative substrates by the brain has been a major emphasis of this laboratory for more than 15-years. The compartmentalized synthesis and utilization of various intermediates for energy and as precursors for neurotransmitters and for structural and functional molecules in the brain requires the continual transfer of substrates between the -various cellular components. Our recent studies provide strong evidence that 3-hydroxybutyrate, acetoacetate, malate and lactate play important roles in this metabolic trafficking. The proposed investigations will evaluate three possible mechanisms by which various effectors regulate the metabolic fates of these substrates. These mechanisms include regulation of the substrate's carrier-mediated z transport systems in individual cells, changes in intermediary metabolite pool sizes and effects on specific enzyme activities involved in their metabolism. Our recent results have demonstrated the presence of a carrier-mediated transport system for 3-hydroxybutyrate in dissociated brain cells which has a distinct developmental profile. In our continuing studies we will further characterize this transport system in cultured astrocytes, neurons and oligodendroglial cells as well as the transport systems for each of the other substrates with respect to types of carriers (high or low affinity), kinetic parameters, and responses to potential effectors such as metabolic intermediates and hormones (T3' insulin, and hydrocortisone). Another group of studies will examine the regulatory mechanisms of ketone body production by brain cells to determine the specific conditions which cause cells to produce or utilize these metabolites. Other studies will examine the production and utilization of malate and lactate in astrocytes, neurons, and oligodendroglia. Crucial information about the factors that contribute to metabolic homeostasis of the developing brain will be derived from these studies. In addition, these studies will increase our understanding of the conditions that lead to mental retardation. For example, our recent research has provided evidence that the transport of ketone bodies is inhibited by compounds that accumulate in several types of mental retardation. An imbalance in the production, transport or utilization of any of the metabolites being studied could lead directly to a dearrangement in the development of the nervous system. Therefore, results from these investigations should provide useful information on which to base effective clinical approaches in the treatment of mental retardation that possibly could include dietary therapy to maintain the proper metabolic homeostasis in the brain.